Nu-(m-benzylthio-phenyl)-anthranilic acid



United States Patent 3,358,019 N-(m-BENZYLTHIO PHENYL} ANTHRANILIC ACID Jelly m and Je n-Pi r e 'Bou qui Base an tGu mh ui audfius av hwa Al sshi ze la assiguurs t 5 1 9 1 8 Ba el, Sw ze land N0 awin Fil d Au .1965, Set-Nu.- 83 4 Claims priority, application Switzerland, May 25, 1956,

3 ;!512 5 10 Claims. (Cl. 260-516) The present application is a Q.I. P application of our copending US. application 'Ser. No. 653,077, filed Apr. 16, 1957, nowabandoned, in which application are described and claimed phenothiazines substituted in the 3- position by a monova-lent sulfur function.

The present application relates to anthranilic acid derivatives used as intermediates in the production of said phenothiazines substituted in the 3-position ..by a monovalent sulfur function. i

The present invention .thus provides anthranilic acid derivatives of general Formula fl:

I COOH I \NH/ S-R in which R signifies a straight or branched chain alkyl radical of 2 to 6 carbon atoms inclusive, or the benzyl radical.

The present invention further provides a process for the production of the compounds I, characterized in that an aniline derivative of general Formula II:

in which R has the above significance, is condensed with an o-halogenobenzoic acid, in which halogeno signifies chlorine, bromine or iodine, preferably in the form of one of its alkali metal salts in a higher alcohol and in the presence of copper bronze.

The anthranilic acid derivatives may be used, as stated above, as intermediates for the production of phenothiazines. They, and their salts, furthermore have valuable pharmacodynamic properties in that they, in addition to having a relatively low toxicity, also exhibit an antiinfiammatory, analgesic and antipyretic activity.

These pharmacological activities were ascertained as follows:

Antiinflammat'ory actz'0n.Rats are infected with mycoplasma (PPLO:pleuropneumonia-like organisms), whereupon arthritis results. The extent of the arthritis is ascertained by means of a function test (i.e., by measuring the time during which the test animals are capable of maintaining their position on a vertical screen). After subsequent subcutaneous administration of the compound to be tested, the above mentioned function test is repeated 1.3 and 5 hours later. A dosage of 30 mg./kg. s.c. of a compound of general Formula I improves the PPLO arthritis of the rat by at least 50%.

Analgesic action.The analgesic activity of the compounds I is tested on mice on a hot plate at a temperature of 56 C. In this test the reaction time of the animal, i.e., the time elapsing between the placing of the animal on the hot plate and the appearance of the first symptoms of pain, is measured and the percentage increase of the reaction time resulting from an intravenous, subcutaneous or oral administration of the compounds I as opposed to control animals which have not been pretreated, is ascertained.

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antipyr ti w ner. 5 .autip r ticacti n o t e smun uu s 11 iz up 't T subcuta eous jui 1 a o a y ,uspensi g,- su t iut new de elpnmenwi If.

The rectal temperature of the rats is then measured, wh teatte the =Q .1PQuud t be te te re a m n ste subcutaneously an the te era u measur a nu a regular intervals. Comparison with control rats to whom no compound oft-he Formnla I is administered shows that said compounds I cause a relatively rapid lowering of the body-temperature.

The anthranilic acid derivatives of Formula 1 and their salts may thus he-used in the treatment of rheumaticillnesses and similar inflammatory diseases.

The sodium, potassium, lithium, ammonium, calcium and magnesium" salts are especially useful. The trialkylammonium'or mono-, dior trialkanol-am-monium salts, e.g., the triethyl-ammonium, ethanol-ammonium, diethauo z ru u u or r ethauq ammq iuaa salts man h w- -ve al b ut lize The anthranilic acid derivatives may be applied perorally in the form of tablets, drages, capsules, ,or parenterally in the form of injection solutions. ,In the case of peroral administration, the free acid is preferably used while, in the case of parenteral administration it is preferable to utilize the solution of a suitable salt.

The daily dosage administered is dependent upon the degree of the illness as .well as upon the condition of the Pa entv1 .1 en al, h weve do a es of rom 0.0 I 1,500 mg. may be administered daily, though a preferable dosage range is from to 300 mg.

The compounds of Formula I are suggested for use as pharmaceuticals on their own or in the form of appropriate medicinal preparations for administration, e.g., orally, enterally or parenterally. In order to produce suitable medicinal preparations the compounds are worked up with organic or inorganic adjuvants which are inert and physiologically acceptable. Examples of such adjuvants are:

Tablets and drages: lactose, starch, talc and stearic acid;

Injectable solutions: water, alcohols, glycerin and vegetable oils.

The preparations may furthermore contain suitable preserving, stabilizing and wetting agents, solubilizers, sweetening and colouring substances and flavourings.

In the following non-limitative example all temperatures are given in degrees centigrade.

EXAMPLE N (m-benzy lthz'o-phenyl) -anfhranilic acid A mixture of 208 g. of the potassium salt of o-chlorobenzoic acid, 254 g. of m-benzylthio-aniline, 10 g. of copper bronze and 1000 cc. of 4-methyl-pentanol-(2) are heated to the boil at reflux while stirring for 5 hours at a bath temperature of g. of sodium carbonate and 1000 cc. of water are subsequently added to the reaction mixture which is then distilled with water vapour. The residue is filtered, cooled and 750 cc. of hydrochloric acid (1:1) are added thereto to Congo red indicator. The carboxylic acid which precipitates in crystalline form is filtered off and dried. After crystallizing twice, each time from a threefold quantity of benzene, the pure N-(m-benzylthio-phenyl)-anthranilic acid having a melting point of 137-139" results.

Potassium salt.-- l0.0 g. of N-(m-benzylthio-phenyl) anthranilic acid and 1.84 g. of potassium hydroxide are dissolved in 60 cc. of boiling isopropanol and .then cooled. After recrystallization of the resulting salt from 60 cc. of isopropanol the pure potassium salt of Q N-(m-benzylthio-phenyl)-anthranilic acid having a melting point of 162-164 results.

Sodium salt.-10.0 g. of N-(m-benzylthio-phenyD- anthranilic acid and 1.31 g. of sodium hydroxide are dissolved in 60 cc. of isopropanol, filtered and made to crystallize by cooling. After recrystallization from 60 cc. of isopropanol the pure sodium salt of N-(m-benzylthiophenyD-anthranilic acid having a melting point of 199'- 201" results.

In a manner analogous to that described above, the following compounds may be produced:

Melting point, deg.

N-(m-methylthio-phenyl)-anthrani1ic acid 139-141 N-(m-ethylthio-phenyl)-anthranilic acid 114-116 N-(m-n-propylthio-phenyl)-anthranilic acid 99-101 N-(m-isopropylthio-phenyl)-anthrani1ic acid 114-116 N-(m-n-butylthio-phenyl)-anthranilic acid 77-79 N-(m-isobutylthio-phenyl)-anthranilic acid 107-109 N-(m-sec.butylthio-phenyl)-anthranilic acid 68-70 N-(m-amylthio-phenyl)-anthranilic acid 64-66 N-(m-hexylthio-phenyl)-anthranilic acid 64-66 The physiologically acceptable salts of the above compounds may also be produced and have the utility here inbefore stated.

What is claimed is:

1. A compound of the formula:

-COOH wherein R signifies a straight or branched chain alkyl of References Cited UNITED STATES PATENTS 1,994,641 3/1935 Haddock et a1. 260-516 2,017,613 10/1935 Veraguth et al. 260516 2,994,640 8/ 1961 Zellner 167--65 3,047,462 7/ 1963 Maillard et al. 16765 3,176,015 3/1965 Jacob et a1 260243 FOREIGN PATENTS 630,842 6/1936 Germany.

OTHER REFERENCES Lehmstedt et al.: Ber. Deut. Chem., vol. 70, pp. 838-849 (1937).

Bourquin et al.: Helv. Chim. Acta, vol. 41, pp. 1061- 1072 (1958).

LORRAINE A. WEINBERGER, Primary Examiner.

R. JACKSON, Examiner.

T. L. GALLOWAY, Assistant Examiner. 

1. A COMPOUND OF THE FORMULA: 